tbuckley/cabot-search huggingface dataset:
Abstract 3752: The role of miR-200 in anaplastic thyroid cancer aggressiveness
Authors: Hugo Huth, César Fuziwara, Edna Kimura
Journal: Cancer Research (2023)

Abstract Anaplastic Thyroid Cancer (ATC) is the most aggressive and lethal of all thyroid cancer histotypes, characterized by undifferentiated, highly proliferative and invasive cells, which are intrinsically resistant to conventional treatment. Deregulation of microRNAs (miRNAs), a group of small non-coding RNAs that post-transcriptionally regulates protein expression, has been linked with cancer development. Specifically, the miR-200 family has been postulated to control the balance between epithelial and mesenchymal cell states through Epithelial-Mesenchymal Transition (EMT), a critical process for tumor metastasis. Previous results showed that miR-200c, a member of miR-200 family, is downregulated in ATC, but the biological effect of its deregulation remains unclear. Therefore, this study aims to evaluate the antitumor effect of miR-200c on ATC cell aggressiveness. Using plasmid overexpression, we induced miR-200c upregulation in KTC2 (KTC2-200c) and SW1736 (SW-200c) cells to analyze its role in cell differentiation, proliferation, migration, and EMT markers expression. Light microscope images showed that KTC-200c and SW-200c cells presented an epithelial morphology in contrast with the control group which displayed mesenchymal morphology. Analysis by qPCR and western blot of KTC-200c and SW-200c cells showed that upregulation of miR-200c expression enhanced mRNA and protein expressions of the epithelial marker E-cadherin, while diminished the mRNAs and protein levels of the mesenchymal markers N-cadherin and ZEB1/2. Additionally, KTC2-200c and SW-200c presented reduced cell colony formation and cell proliferation, and reduced cell migration visualized by wound healing assay and transwell assay. In conclusion, this study evidences the tumor suppressor role of miR-200 in controlling ATC cell aggressiveness. Grants from FAPESP (2021/12284-0, 2019/17282-5, 2019/25116-8) and CNPq (311210/2021-0). Citation Format: Hugo Huth, César Fuziwara, Edna Kimura. The role of miR-200 in anaplastic thyroid cancer aggressiveness. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3752.
Abstract 4299: Gene expression based machine learning classifier to predict and validate cancer type in patient derived xenograft (PDX) models
Authors: Warren Andrews, Long Do, Jonathan Nakashima
Journal: Cancer Research (2023)

Abstract Patient derived xenografts (PDX) are increasingly utilized in translational research and drug development. Characterizing the genomic features of PDX is essential to establishing reliable models for cancer research. Despite great interest, problems remain in PDX tumor data banks including improper cancer type diagnosis and sample mix-ups. In an effort to improve annotation and quality of PDX models, we developed a machine learning model trained on gene expression data from The Cancer Genome Atlas (TCGA). We then applied the model to corresponding data collected from nearly 300 Certis PDX models plus publicly available data from NCI’s Patient-Derived Models Repository (PDMR). The model shows high precision and variable recall and provides a fast and accurate method for cancer type diagnosis. Citation Format: Warren Andrews, Long Do, Jonathan Nakashima. Gene expression based machine learning classifier to predict and validate cancer type in patient derived xenograft (PDX) models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4299.
Abstract 1779: Fourth-generation chimeric antigen receptor T cells targeting mucin 1 against breast cancer
Authors: Kamonlapat Supimon, Thanich Sangsuwannukul, Mutita Junking, Pa-thai Yenchitsomanus
Journal: Cancer Research (2023)

Abstract Breast cancer (BC) is the most common cause of deaths worldwide, which is required effective treatment strategies. The second-generation chimeric antigen receptor (CAR) T cell therapy was approved by U.S. Food and Drug Administration for hematological malignancies, exhibiting impressive efficacy. However, CAR T cell therapy has not been approved in solid tumors and it has intensively been the subjects of research and development. To develop CAR T cell therapy, it is crucial to identify target antigen specifically expressed on tumor cells. Mucin 1 (MUC1) was previously reported to be overexpressed in several tumors. In this study, we examined MUC1 expression in BC tissues and cultured cell lines, and to improve CAR T cell efficiency, we generated fourth-generation anti-MUC1 CAR T cells (αM.CAR4 T cells), containing anti-MUC1 single-chain variable fragment (scFv), three costimulatory molecules (CD28, CD137, CD27) and CD3ζ. High levels of MUC1 expression were observed in the tissues and cell lines. Comparing to second- and third-generations (αM.CAR2 T and αM.CAR3 T cells), the αM.CAR4 T cells showed greater proliferation in the CAR T cell production process. The anti-tumor functions of all CAR T cells were specific to MUC1 expression since their killing activities were illustrated against MUC1-positive but not MUC1-negative BC cells. Interestingly, at low effector to target ratios, the αM.CAR4 T cells exhibited higher tumor cell lysis than those of αM.CAR2 T and αM.CAR3 T cells. Furthermore, after exposure to MUC1-positive BC cells, the αM.CAR4 T cells expressed lower programmed cell death protein 1 (PD-1) level. Taken together, the αM.CAR4 T cells are potential to be further developed for treatments of MUC1-positive BC and other cancers. Citation Format: Kamonlapat Supimon, Thanich Sangsuwannukul, Mutita Junking, Pa-thai Yenchitsomanus. Fourth-generation chimeric antigen receptor T cells targeting mucin 1 against breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1779.
Abstract 6539: Application of optical genome mapping to identify samples with homologous recombination deficiency
Authors: Andy Wing Chun Pang, Kelsea Chang, Nikhil Sahajpal, Daniel Saul, Ravindra Kolhe, Alka Chaubey, Alex Hastie
Journal: Cancer Research (2023)

Abstract Certain cancer treatments, such as the poly (ADP-ribos) polymerase (PARP) inhibitors, have been shown to be effective in killing cancer cells exhibiting genome instability signatures indicative of homologous recombination deficiency (HRD). Hence, these signatures are used as biomarkers to inform treatment decisions and prognosis. There are three measurements of HRD signatures commonly employed: loss of heterozygosity (HRD-LOH), telomeric allelic imbalance (TAI) and large-scale state transition (LST). It has been shown that combining all three scores can better determine the HRD phenotype, leading to a higher clinical impact. Yet current HRD signature tests, used to estimate HRD, have low negative predictive value, and one possible reason is that current genomic technologies lack sensitivity to capture the full extent of somatic genomic rearrangements. Here, optical genome mapping (OGM) was used to detect large structural variants (SVs) and calculate a HRD score. OGM captures high molecular weight DNA to call SVs by aligning these molecules to the public reference genome. OGM can comprehensively detect insertions and deletions &amp;gt;5kbp, inversions, interchromosomal translocations, plus large interstitial copy number variation (CNV) and aneusomies. Subsequently, an automated script was developed to compute the HRD score, which is the summation of the three HRD signatures: HRD-LOH, the number of regions with a loss &amp;gt;15 Mbp but shorter than the whole chromosome; TAI, the number of regions of gain and loss &amp;gt;10Mbp that extend to a subtelomere but do not cross the centromere; and LST, the number of chromosomal breakpoints whose SV size &amp;gt;10Mb but not the whole chromosome. We applied this script on 20 samples of solid tumors and myeloid neoplasms, and the automated scores are concordant with expertly curated scores, confirming the validity of the calculation. We believe that OGM data combined with this automated analysis of HRD signatures is much more sensitive and accurate for detection of HRD signatures and that this will enable more precise prediction of drug response for multiple tumor types. Citation Format: Andy Wing Chun Pang, Kelsea Chang, Nikhil Sahajpal, Daniel Saul, Ravindra Kolhe, Alka Chaubey, Alex Hastie. Application of optical genome mapping to identify samples with homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6539.
Abstract 1982: Exploring the impact of metastatic breast cancer support group in Nigeria
Authors: Runcie C. Chidebe, Theodora Nwosu-Zitta, Mary-Gloria A. Orji, Khadijat Banwo-Fatai, Agha A. Agha, Darlingtina K. Esiaka, Tochukwu C. Orjiakor
Journal: Cancer Research (2023)

Abstract Background: Over 70% of breast cancer patients in Nigeria present metastatic/advanced breast cancer (MBC). An estimated 90% of breast cancer deaths are as a result of metastatic disease, either at diagnosis or recurrence. MBC is associated with severe burden to the patient, family, healthcare delivery system and the society at large. Women living with MBC face many challenges ranging from poor access to MBC information, untreated pain, frequent break-down of radiotherapy machines and absence of peer support. Method: In this research, we set up the first metastatic breast cancer support group in Abuja. The group meet once every month on a face-to-face basis and also uses WhatsApp group for regular meaningful engagement. We explored the impact of the group on the patient’s quality of life (QoL) using a focused group discussion (FGD). Eighteen (18) patients participated in the two sessions of FGD. Result: Many of the patients report that the support group provides a culture of love and strength over their death anxiety, especially meeting other patients who have lived with MBC longer. They also report to have found peer support on the online WhatsApp group. Citation Format: Runcie C. Chidebe, Theodora Nwosu-Zitta, Mary-Gloria A. Orji, Khadijat Banwo-Fatai, Agha A. Agha, Darlingtina K. Esiaka, Tochukwu C. Orjiakor. Exploring the impact of metastatic breast cancer support group in Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1982.
Abstract 3527: WNT5B drives osteosarcoma stemness, metastasis and chemoresistance
Authors: Rachel S. Perkins, Sarocha Suthon, Gustavo A. Miranda-Carboni, Susan A. Krum
Journal: Cancer Research (2023)

Abstract Osteosarcoma is a pediatric bone cancer that has no targeted therapy and has had no treatment advances for the last three decades. Osteosarcoma frequently metastasizes to the lungs, reducing patient survival with metastatic disease to 20% after 5 years. The goal of this study is to describe the function of WNT5B and its signaling pathway in osteosarcoma stem cells, metastasis and chemoresistance and its potential as a therapeutic target. Using RNA sequencing from publicly available datasets and immunohistochemistry on tumor microarrays, we reveal that WNT5B is the most expressed WNT in osteosarcoma patients and correlates with both metastasis and survival. Osteosarcoma is thought to result from a block in differentiation, and based on WNT5B’s role in inhibiting osteoblast differentiation of mesenchymal stem cells from normal bone, we hypothesized a role for WNT5B in osteosarcoma stem cells. In spheroids, we show that both protein and mRNA levels of WNT5B are enhanced in the stem cell population compared to adherent cells. We found that WNT5B upregulates the expression of the stemness gene SOX2 and directs stemness phenotypes, such as sphere forming efficiency, proliferation and migration. We show a reduction in sphere forming efficiency with 143B-WNT5B-knockdown cells compared to parental control cells which can be rescued with re-introduction of WNT5B. Additionally, we show that WNT5B drives proliferation and migration of osteosarcoma stem cells through increasing sphere size and capability to migrate on collagen matrix. Further, WNT5B enhances osteosarcoma chemoresistance to methotrexate. Through revealing a novel role for WNT5B in osteosarcoma cancer stem cells and therapy resistance, we present the WNT5B pathway as a candidate for therapeutically targeting osteosarcoma stem cells in patients. Citation Format: Rachel S. Perkins, Sarocha Suthon, Gustavo A. Miranda-Carboni, Susan A. Krum. WNT5B drives osteosarcoma stemness, metastasis and chemoresistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3527.
Abstract 2811: CDK4/6 inhibition plus radiotherapy enhances anti-tumor immunity in non-small cell lung cancer
Authors: Zhengrong Huang, Jiang Luo, Mengqin Wang, Hongxin Xie, Yuxin Zeng, Yu Yuan, Wan Xiang, Ziyu Jiang, Conghua Xie, Yan Gong
Journal: Cancer Research (2023)

Abstract Lung cancer is the main cause of cancer-related mortality, of which non-small cell lung cancer (NSCLC) accounts for 85%. Abemaciclib, a selective CDK4/6 inhibitor, enhanced the radiosensitivity of NSCLC in vivo and in vitro and improved the prognosis of advanced NSCLC patients according to a Phase I clinical trial. This study aimed to explore the impact of CDK4/6 inhibition combined with irradiation and immunotherapy on NSCLC. The in vivo xenograft tumor mouse model was used to investigate the synergistic effects of CDK4/6 inhibitor abemaciclib and irradiation together with anti-PD-1 antibodies. The tumor infiltrating lymphocytes (TILs) in tumor microenvironment (TME) were analyzed by flow cytometry. The complete blood count and serum tests were used to determine the safety of this combination therapy. The human phospho-kinase array and dual-luciferase report assay were used to study the regulatory mechanisms of abemaciclib and irradiation combination on PD-L1 transcription in NSCLC cells in vitro. Our results indicated the significantly synergistic effects of abemaciclib, irradiation and anti-PD-1 antibodies on NSCLC growth in vivo, accompanied by increased CD8+ T cell infiltration and decreased regulatory T cells and myeloid-derived suppressor cells (MDSCs), suggesting a strong anti-tumor combination of CDK4/6 inhibition, radiotherapy and immunotherapy. This synergistic effect could be partially impaired by CD8 depletion, and alleviated the anemia and inflammation caused by tumor burden without hepatorenal toxicity. Abemaciclib induced PD-L1 transcription through JNK/c-Jun pathway in vitro, which might elevate PD-L1 expression synergistically with irradiation through TBK1/IRF3 pathway. Our studies suggested that CDK4/6 inhibition plus irradiation enhanced anti-tumor immune responses in NSCLC. Together with immunotherapy, the combination of CDK4/6 inhibitors and radiotherapy could lower the doses of individual treatment, thus alleviating the potential toxicity and side effects of CDK4/6 inhibition and irradiation on normal cells. Citation Format: Zhengrong Huang, Jiang Luo, Mengqin Wang, Hongxin Xie, Yuxin Zeng, Yu Yuan, Wan Xiang, Ziyu Jiang, Conghua Xie, Yan Gong. CDK4/6 inhibition plus radiotherapy enhances anti-tumor immunity in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2811.
Abstract 3072: Estrogen receptor β4 regulates chemotherapy resistance and induces cancer stem cells in triple negative breast cancer
Authors: Ayesha Bano, Jessica Stevens, Paulomi S. Modi, Anders Strom, Jan-Ake Gustafsson
Journal: Cancer Research (2023)

Abstract TNBC has the worst prognosis among all breast cancers, and survival in patients with recurrence is rarely beyond 12 months due to acquired resistance to chemotherapy, which is the standard of care for these patients. Our hypothesis is that Estrogen Receptor Beta 1 (ERB1) increases response to chemotherapy but is opposed by ERB4, which it preferentially dimerizes with. The role of ERB1 and ERB4 in influencing chemotherapy sensitivity has never been studied before. CAS9/CRSPR was used to truncate ERB1 Ligand Binding Domain (LBD) and knock down the exon unique to ERB4. We show that the truncated ERB1 LBD in a variety of mutant p53 TNBC cell lines, where ERB1 ligand dependent function was inactivated, had increased resistance to Paclitaxel, whereas the ERB4 knockdown cell line was sensitized to Paclitaxel. We further show that ERB1 LBD truncation as well as treatment with ERB1 antagonist PHTPP leads to increase in the drug efflux transporters. Hypoxia Inducible Factors (HIFs) activate factors involved in pluripotency and regulate the stem cell phenotype, both in normal and cancer cells. Here we show that the ERβ1 and ERB4 regulate these stem cell markers like SOX2, OCT4, and Nanog in an opposing manner; and we further show that this regulation is mediated by HIF. We show the upregulation of cancer cell stemness due to ERB1 LBD truncation is attenuated when HIF1/2a is knocked down by siRNA. Finally we show, an increase in the frequency of breast cancer stem cell population due to ERB1 antagonist using both ALDEFLUOR and SORE6 reporter in SUM159 and MDA-MB-231 cell lines. Since most TNBC cancers are ERβ4 positive, while only a small proportion of TNBC patients are ERβ1 positive, we believe that simultaneous activation of ERß1 with agonists and inactivation of ERB4, in combination with paclitaxel, can be more efficacious and yield better outcome for chemo resistant TNBC patients. Citation Format: Ayesha Bano, Jessica Stevens, Paulomi S. Modi, Anders Strom, Jan-Ake Gustafsson. Estrogen receptor β4 regulates chemotherapy resistance and induces cancer stem cells in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3072.
Abstract 2550: Growth factor-induced cell membrane macroplatforms drive protein kinase signaling for transformed cell growth
Authors: Saverio Alberti, Valeria Relli, Romina Tripaldi, Pasquale Simeone, Emanuela Guerra, Andrea Sacchetti, Paolo Ciufici, Antonino Moschella, Valeria Caiolfa, Moreno Zamai, Marco Trerotola
Journal: Cancer Research (2023)

Abstract Nanoscopic, millisecond-lasting membrane platforms are modeled to constitute main functional signaling units. However, multiple signaling events in cell growth induction, including receptor Tyr-kinase (RTK) stimulation, calcium signaling, cytoplasmic kinase recruitment, operate over much broader space-time frames. Through dynamic confocal/super-resolution/electron-microscopy on living cells, we discovered that signaling competence is acquired through growth factor-induced coalescence of activated growth inducers (RTK, CD9, CD81, CD98, Co-029, CD316, Trop-1, Trop-2, PI3K, PI4K), and downstream effectors (Grb-2, PKCα, ERK, Akt, Src, Syk, ILK, ezrin) into confined segments of the cell membrane (‘docks’), that recursively assemble over hundreds of seconds. Average size (25±5 μm; ~80,000 individual analyses) and lifetime (222±25 sec) of docks extend by orders of magnitude previously recognized space-time frames for cell signaling. Activated/phosphorylated kinases clustered at membrane docks (99% P-Erb-B4; 91% P-Ret; 90% P-PKCα; 90% P-Src). STED super-resolution microscopy revealed up to 10 µm2 signal transducer areas of effector colocalization. Docks &amp;gt;1.0 µm2 accounted for ~90% of colocalizations versus ≈1% of raft-sized domains (&amp;lt;0.005 µm2). FRET-FLIM subsequently indicated that inter-molecular signal transducer interactions are essentially confined at docks. Docks were induced by growth factors (FGF-1, PDGF, EGF&amp;gt;HGF, IGF-1&amp;gt;&amp;gt;SCF/VEGF), were inhibited by Tyr kinase and cytoskeleton inhibitors, and were shown to induce cancer cell proliferation. Citation Format: Saverio Alberti, Valeria Relli, Romina Tripaldi, Pasquale Simeone, Emanuela Guerra, Andrea Sacchetti, Paolo Ciufici, Antonino Moschella, Valeria Caiolfa, Moreno Zamai, Marco Trerotola. Growth factor-induced cell membrane macroplatforms drive protein kinase signaling for transformed cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2550.
Abstract 2553: Elucidation of the downstream signaling of <i>PIK3CA</i> genomic alterations in serous ovarian cancer
Authors: Shibo Zhang, Hei Ip Hong, Victor CY Mak, Yuan Zhou, Panpan Wang, Lydia Wai Ting Cheung
Journal: Cancer Research (2023)

Abstract Genomic aberrations of PIK3CA, which encodes the catalytic subunit p110α of the class IA phosphatidylinositol 3-kinase (PI3K), is frequently observed in cancers. In ovarian cancer of the serous subtype (the most common histotype of the disease), PIK3CA amplification is dominant over single nucleotide mutations in multiple patient cohorts, suggesting the possibility that PIK3CA amplification is an alternative to PIK3CA “hot spot” mutation for serous ovarian tumorigenesis. However, whether PIK3CA amplification and mutation exert the same functional consequences on serous ovarian tumorigenesis remains uncertain. This study aims to explore and compare the functional roles between the two types of PIK3CA gene aberrations on tumorigenicity, cellular signaling, and therapeutic responses in serous ovarian cancer. We confirmed that both PIK3CA amplification and E545K mutation could induce multiple tumorigenic phenotypes in CRISPR/Cas9-mediated E545K knock-in or wild-type PIK3CA overexpressing serous ovarian cancer cell lines. Signaling pathway analyses showed that E545K knock-in cells, but not PIK3CA-overexpressing cells, had the MAPK signaling pathway activated and were sensitive to MAPK pathway inhibition. An induction of AKT phosphorylation and PDK1 phosphorylation was observed in both E545K knock-in cells and wild-type PIK3CA-overexpressing cells. Accordingly, these cells displayed higher sensitivity towards p110α or AKT inhibitors. Intriguingly, in line with previous report which demonstrated YAP as AKT substrate, the activation of AKT associated with an increase in YAP S127 phosphorylation in the knock-in or PIK3CA-overexpressing cells. AKT inhibition suppressed YAP phosphorylation. Corroborating with the role of S127 in nuclear exclusion of YAP, YAP accumulated in the cytoplasm of these cells, leading to reduced transcriptional activity of YAP. While the functional significance of YAP cytoplasmic accumulation is yet to be investigated, our results reveal the common and distinct downstream pathways between PIK3CA amplification and mutation. These findings may be applicable to p110α-targeting therapies in serous ovarian cancer. Citation Format: Shibo Zhang, Hei Ip Hong, Victor CY Mak, Yuan Zhou, Panpan Wang, Lydia Wai Ting Cheung. Elucidation of the downstream signaling of PIK3CA genomic alterations in serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2553.